Population Pharmacokinetics of Losmapimod in Healthy Subjects and Patients with Rheumatoid Arthritis and Chronic Obstructive Pulmonary Diseases

Yang, Shuying; Lukey, Pauline T.; Beerahee, Misba; Hoke, Frank

doi:10.1007/s40262-012-0025-6

Cited by 10 publications

(8 citation statements)

References 14 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The mortality rate of RA in worldwide populations varies from 0.01-0.05%, and prevalence rate is 0.18-1.07% (3). RA is also an impactful disease, resulting in labor loss and disability in China (2).…”

Section: Introductionmentioning

confidence: 99%

(5R)-5-hydroxytriptolide (LLDT-8) prevents collagen-induced arthritis through OPG/RANK/RANKL signaling in a rat model of rheumatoid arthritis

Zeng

Meng

et al. 2016

Experimental and Therapeutic Medicine

View full text Add to dashboard Cite

Abstract. (5R)-5-hydroxytriptolide (LLDT-8) extracts fromTripterygium have anti-inflammatory, antineoplastic and immunity adjustment functions. The present study used a collagen-induced arthritis (CIA) model to evaluate whether LLDT-8 prevents collagen-induced arthritis, and investigated the signaling underlying this. Male Sprague-Dawley rats were induced to generate CIA, mimicking rheumatoid arthritis (RA). The presence of arthritis was determined using RA progression scores. The inflammatory cytokines interleukin (IL)-1β, IL-6 and nuclear factor-κB were detected using enzyme-linked immunosorbent assay kits. Induced nitric oxide synthase (iNOS) and matrix metalloprotease (MMP)-13 protein expression were measured using western blot analysis. Lastly, reverse transcription-quantitative polymerase chain reaction was used to evaluate osteoprotegerin (OPG) and receptor activator of nuclear factor κB (RANK) gene expression. LLDT-8 improved RA progression scores and reduced the incidence and severity of CIA. Furthermore, LLDT-8 administration inhibited collagen-induced inflammation and iNOS protein expression in arthritic rats. The current data indicated that MMP-13 production was suppressed and OPG/RANKL expression was increased by LLDT-8 treatment in the arthritic rat. The present results suggest that LLDT-8 attenuates CIA through OPG/RANK/RANK ligand signaling in a rat model of RA. IntroductionRheumatoid arthritis (RA) is a chronic, systemic autoimmune disease that is characterized by erosive arthrosynovitis (1).The incidence of RA in females is more than that in males, at a ratio of 1:3 (2). The mortality rate of RA in worldwide populations varies from 0.01-0.05%, and prevalence rate is 0.18-1.07% (3). RA is also an impactful disease, resulting in labor loss and disability in China (2). According to US epidemiological investigation over the last 40 years, the difference in mortality rate between RA patients and the general population has increased (4). The risk of cognitive impairment for RA patients is higher than that of the general population (5). The etiology of RA is unclear. Previous studies suggest that RA is associated with genetic factors, infection, immunity and endocrine function (6,7).The main pathological characteristics of RA are hyperplasia of synovial cells and T cell accumulation during inflammation of synovial tissues, accompanied by pannus formation, followed by damage to the cartilage and bone (8). Finally, RA causes joint deformity and functional loss (9). These pathological changes may result from a combination of genetic mutations, activation of protooncogenes, lesions of synoviocytes, release of proinflammatory cytokines by inflammatory cells during infiltration of synovial tissues, chemotactic factors and enzymatic degradation of stromal proteins, amongst other factors (10). The etiology of RA is unclear, but it is universally believed to be a multifactorial disease, associated with genetic, environmental and infective factors (11). Autoimmunity may arise due to genetic factors, or as an ab...

show abstract

Section: Introductionmentioning

confidence: 99%

(5R)-5-hydroxytriptolide (LLDT-8) prevents collagen-induced arthritis through OPG/RANK/RANKL signaling in a rat model of rheumatoid arthritis

Zeng

Meng

et al. 2016

Experimental and Therapeutic Medicine

View full text Add to dashboard Cite

show abstract

“…Losmapimod ( Figure 1A) is a potent p38 MAPK inhibitor currently being developed by GlaxoSmithKline for the treatment of ACS and chronic obstructive pulmonary disease and is also under investigation for use in the treatment of other conditions involving inflammation, including rheumatoid arthritis and neuropathic pain. [10][11][12] As ethnicity may potentially be associated with differences in drug response, it is important to study drugs in subjects from a variety of ethnic backgrounds. Therefore, this study investigated the potential effect of ethnicity on the absorption, distribution, metabolism, and elimination of losmapimod in a group of healthy Japanese subjects.…”

mentioning

confidence: 99%

“…Inhibition of p38 MAPK has the potential to provide clinical benefit in patients presenting with MI through inhibition of inflammation, thereby modulating a mechanism of the disease that has not been addressed fully by currently available treatments. Losmapimod (Figure A) is a potent p38 MAPK inhibitor currently being developed by GlaxoSmithKline for the treatment of ACS and chronic obstructive pulmonary disease and is also under investigation for use in the treatment of other conditions involving inflammation, including rheumatoid arthritis and neuropathic pain …”

mentioning

confidence: 99%

Safety, tolerability, pharmacokinetics, and pharmacodynamics of losmapimod in healthy Japanese volunteers

Ino

Takahashi

Terao

et al. 2015

Clinical Pharm in Drug Dev

View full text Add to dashboard Cite

This phase 1 study characterized the safety, tolerability, pharmacokinetics, and pharmacodynamics of losmapimod and its metabolite GSK198602 following single and repeat doses of oral losmapimod in healthy Japanese volunteers. Subjects (n = 41) received single oral doses of losmapimod (2.5, 7.5, 20 mg) or matching placebo on 3 separate days (n = 20) or losmapimod 7.5 mg or matching placebo twice daily for 14 days (n = 21). Assessments included maximum observed plasma concentration (Cmax ), time to Cmax (Tmax ), apparent terminal-phase half-life (t1/ )2 , area under the curve (AUC), and change in C-reactive protein and phosphorylated heat shock protein 27 levels. No serious adverse events occurred during the study, and there were no safety concerns regarding clinical laboratory parameters, 12-lead electrocardiogram, or vital signs. The losmapimod Tmax was 3-4 hours, and the mean t1/2 was approximately 7.9-9.0 hours, with no appreciable difference in Tmax and apparent clearance following oral dosing between dosing regimens. Single and repeat oral doses of losmapimod were well tolerated in healthy Japanese volunteers. The Tmax of GSK198602 was similar to and t1/2 was slightly longer than those of losmapimod. Approximate dose-proportional increases in exposure to losmapimod and GSK198602 were observed in AUC with single-dose administration. Repeat-dose trough concentrations reached steady state within 2 days, with an observed accumulation ratio of 1.56 and 1.91 for losmapimod and GSK198602, respectively.

show abstract

“… 21 Another population PK meta-analysis that included data from three studies (30 healthy volunteers, 23 subjects with rheumatoid arthritis, and 24 subjects with COPD) showed that although some variation by age, sex, and body weight may be expected in losmapimod PK measures, there was no indication for dose adjustment according to these parameters. 28 …”

Section: Phase I Clinical Studies Of Losmapimodmentioning

confidence: 99%

Emerging treatment options to improve cardiovascular outcomes in patients with acute coronary syndrome: focus on losmapimod

Kragholm¹,

Newby²,

Melloni³

2015

DDDT

View full text Add to dashboard Cite

Each year, despite optimal use of recommended acute and secondary prevention therapies, 4%–5% of patients with acute coronary syndrome (ACS) experience relapse of ACS or other cardiovascular events including stroke, heart failure, or sudden cardiac death after the index ACS. The sudden atherosclerotic plaque rupture leading to an ACS event is often accompanied by inflammation, which is thought to be a key pathogenic pathway to these excess cardiovascular events. Losmapimod is a novel, oral p38 mitogen-activated protein kinase (MAPK) inhibitor that targets MAPKs activated in macrophages, myocardium, and endothelial cells that occur as a part of global coronary vascular inflammation following plaque rupture. This review aims to 1) discuss the pathophysiological pathways through which p38 MAPKs may play key roles in initiation and progression of inflammatory disease and how losmapimod is thought to counteract these p38 MAPKs, and 2) to describe the efficacy and safety data for losmapimod obtained from preclinical studies and randomized controlled trials that support the hypothesis that it has promise as a treatment for patients with ACS.

show abstract

Population Pharmacokinetics of Losmapimod in Healthy Subjects and Patients with Rheumatoid Arthritis and Chronic Obstructive Pulmonary Diseases

Cited by 10 publications

References 14 publications

(5R)-5-hydroxytriptolide (LLDT-8) prevents collagen-induced arthritis through OPG/RANK/RANKL signaling in a rat model of rheumatoid arthritis

(5R)-5-hydroxytriptolide (LLDT-8) prevents collagen-induced arthritis through OPG/RANK/RANKL signaling in a rat model of rheumatoid arthritis

Safety, tolerability, pharmacokinetics, and pharmacodynamics of losmapimod in healthy Japanese volunteers

Emerging treatment options to improve cardiovascular outcomes in patients with acute coronary syndrome: focus on losmapimod

Contact Info

Product

Resources

About